Saturday, August 30, 2008

A Rush of Blood to the Head - How neurons tell blood vessels where the action is

One of the reasons that neuroscience has taken off over the last decade is the emergence of functional Magnetic Resonance Imaging as a tool to non-invasively watch the living human brain in action. But fMRI scans can't directly detect neurons firing - instead, they monitor where blood is flowing in the brain. The brain somehow directs the body's vascular system to bring blood to just those regions of the brain that need it, a "Just In Time" marshalling of resources. And this happens not just in the brain but throughout the body, under direction from the nervous system.

Basically, in order to get blood to flow to a specific region of the body, the diameter of the blood vessels in this region need to increase ("vasodilation"). This reduces the blood pressure and, since liquids always flow from regions of high pressure to regions of low pressure, blood moves into the area of the brain that has dilated blood capilleries. The fMRI detects the fact that there are more oxygen-carrying red blood cells in the area because haemoglobin is high in iron (details). But, how do neurons tell blood vessels what to do in the first place?

From Medical News Today (with thanks to the Marathon of Life blog): 06 Jan 2007 - Scientists at the University of Vermont have clarified the cellular process responsible for signaling regional blood flow changes in the brain, thereby uncovering possible causes for such disorders as stroke, migraine, and Alzheimer’s disease. The study was published November 1, 2006 in the prestigious journal Nature Neuroscience.

To function properly, the brain needs to receive an uninterrupted supply of oxygen and glucose, which is provided through an intricate network of blood vessels in the brain. Different parts of the brain are engaged by every activity, such as analytical thought, piano playing, seeing, hearing, walking, and these regions then require a rapid elevation of blood flow to meet the increased metabolic needs of the relevant brain cells (neurons). Though this cellular activity can be visualized in modern-day functional brain scans, the mechanisms by which these neurons signal blood vessels to dilate and increasing blood flow remain largely unknown, and are central to understanding brain function.

The diameter of blood vessels in the brain can be modulated by extracellular potassium, a common element present inside and outside all cells of the body. Such modulation of vessel diameter permits changes in blood flow to occur in the brain, as well as in other organs and tissues. With this knowledge, lead study author Mark Nelson, Ph.D., professor and chair of pharmacology at the University of Vermont, set out to determine whether the diameter of cerebral blood vessels in the brain could be modulated under physiological conditions by external potassium ions. To accomplish this, he and his research team studied the communication that takes place between neurons and blood vessels in mouse and rat brains.

The research team discovered early on that neuronal activity appeared to be communicated to the blood vessels through intermediary cells known as astrocytes. Astrocytes, which comprise about half the brain, had not been thought to play an active role in brain processes, and were thought to serve as the "glue" of the brain. One end of an individual astrocyte forms extensive contacts with thousands of neurons, while the other end surrounds and encases blood vessels. In this way, astrocytes are capable of integrating information from a large number of neurons and translating this information into distinct physiological outcomes, including modulation of blood flow.

The research team found that a wave of calcium ions moves through the astrocyte from the point of contact with the active neuron(s) to the 'endfeet' of the astrocyte that encase the blood vessel. This increase in calcium at the endfeet activates a calcium-sensitive protein, known as a potassium (BK) channel, which permits potassium ions to pour out of the astrocytes onto the adjacent muscle cells in the brain artery. The diameter of a blood vessel is controlled by smooth muscle cells in the walls of the blood vessel, which in turn are controlled by 'inward rectifier' potassium ion channels. When there is a small elevation of external potassium, the activity of these channels increases, causing smooth muscle cells to become less excitable, resulting in relaxation of the cells, dilation of vessels, and hence an increase in local blood flow. Activation of a single astrocyte endfoot was found to be sufficient to dilate a blood vessel.

This ability to direct where the blood flows is not limited to just the brain. From Dr. Joseph LeDoux's book "The Emotional Brain": According to [Walter] Cannon's hypothesis, the flow of blood is redistributed to the body areas that will be active during an emergency situation so that energy supplies, which are carried in the blood, will reach the critical muscles and organs. In fighting, for example, the muscles will need energy more than the internal organs (the energy used for digestion can be sacrificed for the sake of muscle energy during a fight). The emergency reaction, or "fight or flight response," is thus an adaptive response that occurs in anticipation of, and in the service of, energy expenditure, as is often the case in emotional states.
As always, Nature's engineering prowess is truly awe inspiring!

Even though fMRI is a huge advance in our ability to peer inside the inner workings of the mind, it still has some severe limitations. There's actually a 1-2 second delay between the time a neuron fires and the time the blood vessels react, which means that the fMRI has lousy time resolution. From "The Movie in Your Head" by Christof Koch (Scientific American Mind Vol 16, Number 3, 2005): If, in fact, changing coalitions of larger neuron groups are the neuronal correlates of consciousness, our state-of-the-art research techniques are inadequate to follow this process. Our methods either cover large regions of the brain at a crude temporal resolution (such as fMRI, which tracks sluggish power consumption at timescales of seconds), or we register precisely (within one millisecond) the firing rate of one or a handful of neurons out of billions (microelectrode recording). We need fine-grained instruments that cover all of the brain to get a picture of how widely scattered groups of thousands of neurons work together.

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